Butanedioic acid, 2,3-dihydroxy- [R-(R*,R*)]-,C12-13-branched alkyl esters

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

(Q)SAR

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Secondary sources assessed to provide reliable background information related to chemical groups/classes

Justification for type of information:

QSAR prediction

Qualifier:

no guideline required

Principles of method if other than guideline:

Compilation of accepted pharmacological and toxicological principles for the substance classes of esters, alcohols, and acids

GLP compliance:

not specified

Absorption

In general, branched-chain aliphatic acyclic esters, alcohols, aldehydes and acids are rapidly absorbed from the gastrointestinal tract (Semino 1998a, b).

 

Biotransformation

Esters

Esters are rapidly hydrolysed in vivo in various organs by ubiquitous esterases. Hydrolysis occurs already in the gastrointestinal tract and proceeds in blood, liver, and other organs (Semino 1998a).

Alcohols

Alcohol dehydrogenase pathway

Long chain saturated primary alcohols undergoe oxidation by alcohol dehydrogenase (ADH) to the corresponding aldehyde followed by further oxidation by aldehyde dehrogenase (AlDH) to isododecanoic acid and isotridecanoic acid. The oxidation rate depends on the Michaelis constant (Km) of the alcohol for the reaction catalyzed by ADH. The Km values depend on the chain length (Km: C2< C1, C3<C4<C5<C6<C7<C8<C9<C10 etc.) and possibly also on steric hindrance due to bulky side chains (Eisenbrand & Metzler, 2002).

Alternative pathways

The proportion of alternative pathways increases with decreasing affinity to ADH (and, therefore, low reaction rates), and increasing dose, chain length and branch grade. Then, chain oxidations (omega- or omega-1oxidation) result in polyols which may be further oxidized to carbonic or dicarbonic acids, or keto acids, etc..

Acids

Branched carboxylic acids can undergoe degradation via ß-oxidation preferably in the longer chain to yield shorter fragments. These can be further metabolised in the fatty acid pathway and the citrate cycle. ß-Oxidation and further usage in the citrate cycle proceeds easily for linear alcohols and branched alcohols bearing a methyl group/alkyl substituent at even positions. Methyl groups(alkyl substituents at uneven positions, inhibit ß-oxidation, which favours alternative metabolic pathways (oxidation at other positions) (Semino, 1998b).

 

Conjugation

(Hydroxy-) acids may be conjugated, e.g. glucuronidated or sulfated, and the resulting esters may subsequently be excreted via urine or bile. The conjugates may be cleaved in the gut, which opens the possibility of re-absorption of the more lipophilic alcohol moiety, distribution in the body etc. (entero-hepatic circulation).

Conclusions:

Esters will be rapidly absorbed from the GI-tract either intact or already hydrolised into acid and alcohol. Biotransformation will be governed by hydrolysis as first step followed by oxidation reactions of the alcohol and subsequently the aldehyde and acid. In addition, oxidation at the alkyl fraim will occur. Conjugation is expected followed by urinary and biliary excretion.

Executive summary:

Esters will be rapidly absorbed from the GI-tract either intact or already hydrolised into acid and alcohol. Biotransformation will be governed by hydrolysis as first step followed by oxidation reactions of the alcohol and subsequently the aldehyde and acid. In addition, oxidation at the alkyl fraim will occur. Conjugation is expected followed by urinary and biliary excretion.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The substance is a diester of a dicarboxylic acid consisting of 2,3 - dihydroxybutanedioic acid (C4 carbon frame) and isododecyl alcohols and isotridecyl alcohols with a branched carbon chain (n = 13 and n = 12). Accordingly, the substance is expected to show the typical characteristics of an ester. In vivo, esters are hydrolysed by ubiquitous hydrolases to alcohol and carboxylic acid. In case of diesters, this operation will proceed in two steps resulting first in a monoester. Isododecyl alcohol and Isotridecyl alcohol and 2,3 -dihydroxybutanedioic acid, formed by hydrolysis of the substance, will then follow metabolic pathways typical for alcohols and carboxylic acids.

 

Given the background information on aliphatic saturated long chain esters, alcohols and acids, the following properties and metabolic pathways are expected for the test substance.

Absorption:

Butanedioic acid, 2,3 -dihydroxy-[R-(R*, R*)]-, C12 -C13 -branched) alkyl esters is already hydrolysed in the gastro-intestinal tract and it is rapidly either as such or in form of the alcohol, isododecyl alcohol and/or isotridecyl alcohol and the acid, 2,3 -dihydroxybutanedioic acid (tartaric acid). The dermal absorption is expected to be slow.

Biotransformation: The substance is expected to hydrolyse rapidly in vivo to isododecyl alcohol and isotridecyl alcohol and 2,3 -dihydroxybutanedioic acid. The alcohol will be oxidised by alcohol dehydrogenase and aldehyde dehydrogenase to the corresponding aldehyde and carboxylic acid. Isododecyl alcohol and Isotridecyl alcohol are not expected to be good substrates for ADH and AlDH, due to their branched bulky structure. ß-Oxidation of the carboxylic acid may be hindered by methyl/alkyl substituents at uneven positions, forcing oxidation at other positions and preventing further degradation in the citrate cycle. Therefore, significant chain hydroxylation and conjugation reactions of the alcohol and of other metabolic oxidation products are expected to account for the majority of the biotransformation.

Excretion of polar metabolites and conjugates may occur via urine and bile and is estimated to be substantial. Entero-hepatic circulation of metabolites excreted via bile is likely to occur (Eisenbrand 2002).

Metabolites Alcohols, C12 -C13, branched

The initial step in the mammalian metabolism of primary alcohols is the oxidation to the corresponding carboxylic acid, with the corresponding aldehyde being a transient intermediate. These carboxylic acids are susceptible to further degradation via acyl-CoA intermediates by the mitochondrial ß-oxidation process. This mechanism removes C2 units in a stepwise process and linear acids are more efficient in this process than the corresponding branched acids. In the case of unsaturated carboxylic acids, cleavage of C2-units continues until a double bond is reached. Since double bonds in unsaturated fatty acids are in the cis-configuration, whereas the unsaturated acyl-CoA intermediates in the ß-oxidation cycle are trans, an auxiliary enzyme, enoyl-CoA isomerase catalyses the shift from cis to trans. Thereafter, ß-oxidation continues as with saturated carboxylic acids (WHO, 1999). An alternative metabolic pathway for aliphatic acids exists through microsomal degradation via Omega-or Omega–1 oxidation followed by β-oxidation. This mechanism provides an efficient stepwise chain-shortening pathway for branched aliphatic acids (Verhoeven, et al., 1998). The acids formed from the longer chained aliphatic alcohols can also enter the lipid biosynthesis and may be incorporated in phospholipids and neutral lipids (Bandi et al, 1971and Mukherjee et al. 1980). A small fraction of the aliphatic alcohols may be eliminated unchanged or as the glucuronide conjugate (Kamil et al., 1953). Similar to the dermal absorption potential, it is expected that orally administered aliphatic alcohols also show a chain-length dependant potential for gastro-intestinal absorption, with shorter chain aliphatic alcohols having a higher absorption potential than longer chain alcohols. With regards to the blood-brain barrier a chain-length dependant absorption potential exists with the lower aliphatic alcohols and acids more readily being taken up than aliphatic alcohols/acids of longer chain-length (Gelman, 1975). Taking into account the efficient biotransformation of the alcohols and the physico-chemical properties of the corresponding carboxylic acids the potential for elimination into breast milk is considered to be low. The long chain aliphatic carboxylic acids are efficiently eliminated and aliphatic alcohols are therefore not expected to have a tissue retention or bioaccumulation potential (Bevan, 2001). Longer chained aliphatic alcohols within this category may enter common lipid biosynthesis pathways and will be indistinguishable from the lipids derived from other sources (including dietary glycerides) (Kabir, 1993; 1995a,b). A comparison of the linear and branched aliphatic alcohols shows a high degree of similarity in biotransformation. For both sub-categories the first step of the biotransformation consists of an oxidation of the alcohol to the corresponding carboxylic acids, followed by a stepwise elimination of C2 units in the mitochondrial β-oxidation process. The metabolic breakdown for both the linear and mono-branched alcohols is highly efficient and involves processes for both sub-groups of alcohols. The presence of a side chain does not terminate the β-oxidation process, however in some cases a single Carbon unit is removed before the C2 elimination can proceed. In summary, long chained alcohols are generally highly efficiently metabolised and there is limited potential for retention or bioaccumulation for the parent alcohols and their biotransformation products.

Metabolite Tartaric acid:

Data exist on the excretion of L(+) tartaric acid in the urine of rat, guinea pigs, dog, rabbit and man after peroral administration (Underhill et al., 1931 a,b). These studies conclude that the species can be divided in two groups: rats, dogs, and  rabbits excrete 70-100 % of the dose and guinea pigs and humans excrete only 10-20 % of the dose. The decomposition of tartaric acid by the intestinal flora was implicated as the cause for the low recovery in the latter two species. The recovery of L(+)-tartaric acid in the urine of humans has been reported to be only some 20 %.

The results obtained after administration of L(+)-tartaric acid confirm the earlier observation that rats and guinea pigs handle the compound in different ways. The same difference was seen with the D(-)-isomer as well. The pig held an intermediate position in the abilitiy to excrete tartaric acids. Only in the rat was there a difference in the ability to excrete the two isomers, with a lower recovery of the D(-)-form compared to the L(+)-form. Destruction of tartaric acid by the intestinal flora has been implicated as a cause for the difference between rat and guinea pig. however, when the acids were incubated with caecal extracts from both species, no such difference in the ability to decompose the acids was observed. In the guinea pig the remarkable low recoveries of both isomers were associated with marked kidney damage, while this effect has never been described in the rat after administration of L(+)-tartaric acid. In the pig which holds an intermediate position a slight kidney effect has been noted after administration of L(+)-tartaric acid. These results may indicate that some correlation exists between low recovery in urine and kidney damage.

Underhill, F.P., Leonard, C.S., Gross, E.G., Jaleski, T.C., Journal of Pharmacology and Experimental Therapeutics, 43, 359 (1931a)

Underhill, F.P., Petermann, F.I., Jaleski, T.C., Leonard, C.S.,Journal of Pharmacology and Experimental Therapeutics, 43, 381 (1931b)